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BACKGROUND: Avelumab first-line (1 L) maintenance is a standard of care for advanced urothelial carcinoma (aUC) based on the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab 1 L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in patients who were progression free after receiving 1 L platinum-containing chemotherapy. Here, we comprehensively screened JAVELIN Bladder 100 trial datasets to identify prognostic factors that define subpopulations of patients with longer or shorter OS irrespective of treatment, and predictive factors that select patients who could obtain a greater OS benefit from avelumab 1 L maintenance treatment. METHODS: We performed machine learning analyses to screen a large set of baseline covariates, including patient demographics, disease characteristics, laboratory values, molecular biomarkers, and patient-reported outcomes. Covariates were identified from previously reported analyses and established prognostic and predictive markers. Variables selected from random survival forest models were processed further in univariate Cox models with treatment interaction and visually inspected using correlation analysis and Kaplan-Meier curves. Results were summarized in a multivariable Cox model. RESULTS: Prognostic baseline covariates associated with OS included in the final model were assignment to avelumab 1 L maintenance treatment, Eastern Cooperative Oncology Group performance status, site of metastasis, sum of longest target lesion diameters, levels of C-reactive protein and alkaline phosphatase in blood, lymphocyte proportion in intratumoral stroma, tumor mutational burden, and tumor CD8+ T-cell infiltration. Potential predictive factors included site of metastasis, tumor mutation burden, and tumor CD8+ T-cell infiltration. An analysis in patients with PD-L1+ tumors had similar findings to those in the overall population. CONCLUSIONS: Machine learning analyses of data from the JAVELIN Bladder 100 trial identified potential prognostic and predictive factors for avelumab 1 L maintenance treatment in patients with aUC, which warrant further evaluation in other clinical datasets.
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Anticuerpos Monoclonales Humanizados , Aprendizaje Automático , Neoplasias de la Vejiga Urinaria , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Femenino , Pronóstico , Anciano , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Persona de Mediana Edad , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/patología , Quimioterapia de Mantención/métodos , Antineoplásicos Inmunológicos/uso terapéutico , Supervivencia sin Progresión , Biomarcadores de TumorRESUMEN
BACKGROUND: Patients treated with immune checkpoint inhibitors (ICIs) may experience pseudoprogression, which can be classified as progressive disease (PD) by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and could lead to inappropriate treatment discontinuation. Immune-response criteria were developed to better capture novel response patterns seen with ICIs. METHODS: We pooled data from 1765 patients with 12 types of advanced solid tumors treated with avelumab (an anti-programmed death ligand 1 (PD-L1) monoclonal antibody) monotherapy in the JAVELIN Solid Tumor and JAVELIN Merkel 200 trials, conducted a comparative analysis of tumor assessments by investigators according to RECIST 1.1 and immune-related RECIST (irRECIST), and evaluated the correlation between progression-free survival (PFS) and overall survival (OS). RESULTS: In total, 147 patients (8.3%) had a best overall response (BOR) of PD by RECIST 1.1 but had immune-related disease control by irRECIST (defined as immune-related BOR (irBOR) of immune-related stable disease or better). This discordance was seen irrespective of PD-L1 status and observed across all tumor types. Overall, PFS and immune-related PFS showed similar imputed rank correlations with OS. CONCLUSIONS: The use of irRECIST identified a subset of patients with a BOR of PD by RECIST 1.1 but an irBOR of immune-related disease control by irRECIST with a distinctive survival curve, thereby providing more clinically relevant information than RECIST 1.1 alone. However, as a surrogate endpoint for OS in the whole population, immune-related PFS by irRECIST did not show improved predictive value compared with PFS by RECIST 1.1.
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Antígeno B7-H1 , Neoplasias , Antígeno B7-H1/uso terapéutico , Humanos , Inhibidores de Puntos de Control Inmunológico , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores SólidosRESUMEN
Background: This study examined patients with advanced non-small-cell lung cancer who received long-term avelumab (anti-PD-L1) in a large phase Ib trial (JAVELIN Solid Tumor). Methods: Patients receiving >2 years of avelumab were reviewed and exploratory descriptive analyses were conducted. Results: Individuals with varying baseline characteristics who had received up to 6 years of avelumab were reviewed. Overall, 37/340 (10.9%) had received ≥2 years of treatment; in this subgroup, best response was complete response in 5.4%, partial response in 59.5% and stable disease in 29.7%; 51.4% had continued treatment beyond disease progression. Conclusions: In this study, 11% of patients with advanced non-small-cell lung cancer received ≥2 years of avelumab treatment and experienced prolonged response or continued clinical benefit. Clinical Trial Registration: NCT02395172 (ClinicalTrials.gov).
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patologíaRESUMEN
Avelumab (anti-PD-L1) is an approved anticancer treatment for several indications. The JAVELIN Gastric 100 phase III trial did not meet its primary objective of demonstrating superior overall survival (OS) with avelumab maintenance versus continued chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer; however, the OS rate was numerically higher with avelumab at timepoints after 12 months. Machine learning (random forests, SIDEScreen, and variable-importance assessments) was used to build models to identify prognostic/predictive factors associated with long-term OS and tumor growth dynamics (TGDs). Baseline, re-baseline, and longitudinal variables were evaluated as covariates in a parametric time-to-event model for OS and Gompertzian population model for TGD. The final OS model incorporated a treatment effect on the log-logistic shape parameter but did not identify a treatment effect on OS or TGD. Variables identified as prognostic for longer OS included older age; higher gamma-glutamyl transferase (GGT) or albumin; absence of peritoneal carcinomatosis; lower neutrophil-lymphocyte ratio, lactate dehydrogenase, or C-reactive protein (CRP); response to induction chemotherapy; and Eastern Cooperative Oncology Group performance status of 0. Among baseline and time-varying covariates, the largest effects were found for GGT and CRP, respectively. Liver metastasis at re-baseline predicted higher tumor growth. Tumor size after induction chemotherapy was associated with number of metastatic sites and stable disease (vs. response). Asian region did not impact OS or TGD. Overall, an innovative workflow supporting pharmacometric modeling of OS and TGD was established. Consistent with the primary trial analysis, no treatment effect was identified. However, potential prognostic factors were identified.
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Anticuerpos Monoclonales Humanizados , Neoplasias Gástricas , Humanos , Aprendizaje Automático , Pronóstico , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention-to-treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment-policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross-industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation.
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Neoplasias , Cambio de Tratamiento , Interpretación Estadística de Datos , Humanos , Oncología Médica , Neoplasias/tratamiento farmacológico , Proyectos de InvestigaciónRESUMEN
OBJECTIVES: The JAVELIN Lung 200 phase 3 trial did not meet its primary endpoint of improving overall survival (OS) with avelumab vs docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report post hoc analyses assessing the effects of subsequent immune checkpoint inhibitor (ICI) treatment on OS. MATERIAL AND METHODS: Patients with stage IIIB/IV NSCLC progressed following platinum-doublet therapy were randomized to receive avelumab or docetaxel. OS was analyzed in the PD-L1+ population (≥1% of tumor cells) and full analysis set (PD-L1+ or PD-L1-). Effects of subsequent ICI (after permanent discontinuation of study treatment) on OS were analyzed using a preplanned naive sensitivity analysis and post hoc inverse probability of censoring weighting (IPCW) analysis. Subgroups with or without subsequent ICI treatment were analyzed using descriptive statistics. RESULTS: In the avelumab and docetaxel arms, a subsequent ICI was received by 16/396 (4.0 %) and 104/396 (26.3 %) after a median of 10.5 months (range, 3.9-20.4) and 5.7 months (range, 0.1-24.4), respectively. Some subgroups showed trends for higher subsequent ICI treatment, including patients with non-squamous NSCLC (avelumab arm, 4.3 % vs docetaxel arm, 32.1 %) or with a baseline ECOG performance status of 0 (6.3 % vs 31.3 %); those enrolled in the early recruitment wave (11.6 % vs 54.3 %), or enrolled in the US/Western Europe (2.8 % vs 45.5 %) or Asia (11.0 % vs 35.4 %); and non-white patients (10.1 % vs 35.0 %). The hazard ratio for OS with avelumab vs docetaxel was lower in the IPCW analysis than in the naive sensitivity analysis (PD-L1+ population: 0.80 [95 % CI, 0.62-1.04] vs 0.86 [95 % CI, 0.68-1.09], respectively). CONCLUSION: In the JAVELIN Lung 200 trial, avelumab showed clinical activity as second-line treatment for patients with advanced NSCLC. Post hoc analyses suggest that the primary OS analysis may have been confounded by subsequent ICI use in the docetaxel arm. ClinicalTrials.gov identifier: NCT02395172.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados , Asia , Docetaxel/uso terapéutico , Europa (Continente) , Humanos , Pulmón , Neoplasias Pulmonares/tratamiento farmacológico , Platino (Metal)/uso terapéuticoRESUMEN
We investigate the source detection problem in epidemiology, which is one of the most important issues for control of epidemics. Mathematically, we reformulate the problem as one of identifying the relevant component in a multivariate Gaussian mixture model. Focusing on the study of cholera and diseases with similar modes of transmission, we calibrate the parameters of our mixture model using human mobility networks within a stochastic, spatially explicit epidemiological model for waterborne disease. Furthermore, we adopt a Bayesian perspective, so that prior information on source location can be incorporated (e.g., reflecting the impact of local conditions). Posterior-based inference is performed, which permits estimates in the form of either individual locations or regions. Importantly, our estimator only requires first-arrival times of the epidemic by putative observers, typically located only at a small proportion of nodes. The proposed method is demonstrated within the context of the 2000-2002 cholera outbreak in the KwaZulu-Natal province of South Africa.
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Transmisión de Enfermedad Infecciosa , Epidemias , Modelos Estadísticos , Vigilancia en Salud Pública/métodos , Teorema de Bayes , Cólera/epidemiología , Cólera/prevención & control , Cólera/transmisión , Biología Computacional , Trazado de Contacto , Brotes de Enfermedades/prevención & control , Brotes de Enfermedades/estadística & datos numéricos , Transmisión de Enfermedad Infecciosa/prevención & control , Transmisión de Enfermedad Infecciosa/estadística & datos numéricos , Epidemias/prevención & control , Epidemias/estadística & datos numéricos , Humanos , Dinámica Poblacional , Sudáfrica , ViajeRESUMEN
BACKGROUND: Adverse events (AEs) of special interest that arise during treatment with immune checkpoint inhibitors, including immune-related AEs (irAEs), have been reported to be associated with improved clinical outcomes. We analyzed patients treated with avelumab from the JAVELIN Solid Tumor and Merkel 200 trials, examining the association between AEs and efficacy while adjusting for confounding factors such as treatment duration and event order. METHODS: We analyzed efficacy and safety data from 1783 patients treated with the programmed death ligand 1 inhibitor avelumab who were enrolled in expansion cohorts of the JAVELIN Solid Tumor and Merkel 200 trials. To analyze the association between irAEs and efficacy with regard to survival, we used a time-dependent Cox model with time-varying indicators for irAEs, as well as multistate models that accounted for competing risks and time inhomogeneity. RESULTS: 295 patients (16.5%) experienced irAEs and 454 patients (25.5%) experienced infusion-related reactions. There was a reduced risk of death in patients who experienced irAEs compared with those who did not (HR 0.71, 95% CI 0.59 to 0.85) using the time-dependent Cox model. The multistate model did not suggest that the occurrence of irAEs could predict response; however, it predicted a higher chance of irAEs occurring after a response. No association was observed between response and infusion-related reactions. CONCLUSIONS: Patients who experience irAEs showed improved survival. Although irAEs are not predictors for response to immune checkpoint inhibitors, increased vigilance for irAEs is needed after treatment with avelumab. TRIAL REGISTRATION NUMBERS: NCT01772004 and NCT02155647.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos Inmunológicos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma. METHODS: Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome. RESULTS: 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24-43), and median treatment duration was 2.8 months (range 0.5-42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses. CONCLUSIONS: After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Células Transicionales/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Platino (Metal)/farmacologíaRESUMEN
PURPOSE: A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the chemotherapy setting. MATERIALS AND METHODS: Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets. RESULTS: The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.
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Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Nomogramas , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carboplatino/farmacología , Carboplatino/uso terapéutico , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/secundario , Cisplatino/farmacología , Cisplatino/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Conjuntos de Datos como Asunto , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Medición de Riesgo/métodos , Factores de Tiempo , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/patologíaRESUMEN
The analysis of genome-wide association studies (GWAS) benefits from the investigation of biologically meaningful gene sets, such as gene-interaction networks (pathways). We propose an extension to a successful kernel-based pathway analysis approach by integrating kernel functions into a powerful algorithmic framework for variable selection, to enable investigation of multiple pathways simultaneously. We employ genetic similarity kernels from the logistic kernel machine test (LKMT) as base-learners in a boosting algorithm. A model to explain case-control status is created iteratively by selecting pathways that improve its prediction ability. We evaluated our method in simulation studies adopting 50 pathways for different sample sizes and genetic effect strengths. Additionally, we included an exemplary application of kernel boosting to a rheumatoid arthritis and a lung cancer dataset. Simulations indicate that kernel boosting outperforms the LKMT in certain genetic scenarios. Applications to GWAS data on rheumatoid arthritis and lung cancer resulted in sparse models which were based on pathways interpretable in a clinical sense. Kernel boosting is highly flexible in terms of considered variables and overcomes the problem of multiple testing. Additionally, it enables the prediction of clinical outcomes. Thus, kernel boosting constitutes a new, powerful tool in the analysis of GWAS data and towards the understanding of biological processes involved in disease susceptibility.
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Algoritmos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Modelos Genéticos , Simulación por Computador , Redes Reguladoras de Genes , Humanos , Tamaño de la MuestraRESUMEN
In 2011, a large outbreak of entero-hemorrhagic E. coli (EHEC) and hemolytic uremic syndrome (HUS) occurred in Germany. The City of Hamburg was the first focus of the epidemic and had the highest incidences among all 16 Federal States of Germany. In this article, we present epidemiological characteristics of the Hamburg notification data. Evaluating the epicurves retrospectively, we found that the first epidemiological signal of the outbreak, which was in form of a HUS case cluster, was received by local health authorities when already 99 EHEC and 48 HUS patients had experienced their first symptoms. However, only two EHEC and seven HUS patients had been notified. Middle-aged women had the highest risk for contracting the infection in Hamburg. Furthermore, we studied timeliness of case notification in the course of the outbreak. To analyze the spatial distribution of EHEC/HUS incidences in 100 districts of Hamburg, we mapped cases' residential addresses using geographic information software. We then conducted an ecological study in order to find a statistical model identifying associations between local socio-economic factors and EHEC/HUS incidences in the epidemic. We employed a Bayesian Poisson model with covariates characterizing the Hamburg districts as well as incorporating structured and unstructured spatial effects. The Deviance Information Criterion was used for stepwise variable selection. We applied different modeling approaches by using primary data, transformed data, and preselected subsets of transformed data in order to identify socio-economic factors characterizing districts where EHEC/HUS outbreak cases had their residence.
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Infecciones por Escherichia coli/epidemiología , Escherichia coli O104 , Síndrome Hemolítico-Urémico/epidemiología , Modelos Biológicos , Programas Informáticos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Brotes de Enfermedades , Femenino , Alemania/epidemiología , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Factores Sexuales , Factores SocioeconómicosRESUMEN
The key challenge during food-borne disease outbreaks, e.g. the 2011 EHEC/HUS outbreak in Germany, is the design of efficient mitigation strategies based on a timely identification of the outbreak's spatial origin. Standard public health procedures typically use case-control studies and tracings along food shipping chains. These methods are time-consuming and suffer from biased data collected slowly in patient interviews. Here we apply a recently developed, network-theoretical method to identify the spatial origin of food-borne disease outbreaks. Thereby, the network captures the transportation routes of contaminated foods. The technique only requires spatial information on case reports regularly collected by public health institutions and a model for the underlying food distribution network. The approach is based on the idea of replacing the conventional geographic distance with an effective distance that is derived from the topological structure of the underlying food distribution network. We show that this approach can efficiently identify most probable epicenters of food-borne disease outbreaks. We assess and discuss the method in the context of the 2011 EHEC epidemic. Based on plausible assumptions on the structure of the national food distribution network, the approach can correctly localize the origin of the 2011 German EHEC/HUS outbreak.
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In infectious disease epidemiology, statistical methods are an indispensable component for the automated detection of outbreaks in routinely collected surveillance data. So far, methodology in this area has been largely of frequentist nature and has increasingly been taking inspiration from statistical process control. The present work is concerned with strengthening Bayesian thinking in this field. We extend the widely used approach of Farrington et al. and Heisterkamp et al. to a modern Bayesian framework within a time series decomposition context. This approach facilitates a direct calculation of the decision-making threshold while taking all sources of uncertainty in both prediction and estimation into account. More importantly, with the methodology it is now also possible to integrate covariate processes, e.g. weather influence, into the outbreak detection. Model inference is performed using fast and efficient integrated nested Laplace approximations, enabling the use of this method in routine surveillance at public health institutions. Performance of the algorithm was investigated by comparing simulations with existing methods as well as by analysing the time series of notified campylobacteriosis cases in Germany for the years 2002-2011, which include absolute humidity as a covariate process. Altogether, a flexible and modern surveillance algorithm is presented with an implementation available through the R package 'surveillance'.
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Algoritmos , Infecciones por Campylobacter/diagnóstico , Infecciones por Campylobacter/epidemiología , Campylobacter/aislamiento & purificación , Brotes de Enfermedades , Monitoreo Epidemiológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Teorema de Bayes , Infecciones por Campylobacter/microbiología , Niño , Preescolar , Reacciones Falso Positivas , Femenino , Alemania/epidemiología , Humanos , Lactante , Recién Nacido , Masculino , Cadenas de Markov , Persona de Mediana Edad , Adulto JovenRESUMEN
Biological pathways provide rich information and biological context on the genetic causes of complex diseases. The logistic kernel machine test integrates prior knowledge on pathways in order to analyze data from genome-wide association studies (GWAS). In this study, the kernel converts the genomic information of 2 individuals into a quantitative value reflecting their genetic similarity. With the selection of the kernel, one implicitly chooses a genetic effect model. Like many other pathway methods, none of the available kernels accounts for the topological structure of the pathway or gene-gene interaction types. However, evidence indicates that connectivity and neighborhood of genes are crucial in the context of GWAS, because genes associated with a disease often interact. Thus, we propose a novel kernel that incorporates the topology of pathways and information on interactions. Using simulation studies, we demonstrate that the proposed method maintains the type I error correctly and can be more effective in the identification of pathways associated with a disease than non-network-based methods. We apply our approach to genome-wide association case-control data on lung cancer and rheumatoid arthritis. We identify some promising new pathways associated with these diseases, which may improve our current understanding of the genetic mechanisms.
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Algoritmos , Epistasis Genética/genética , Redes Reguladoras de Genes/genética , Estudio de Asociación del Genoma Completo/métodos , Redes y Vías Metabólicas/genética , Modelos Genéticos , Transducción de Señal/genética , Artritis Reumatoide/genética , Simulación por Computador , Humanos , Modelos Lineales , Neoplasias Pulmonares/genética , Factores de RiesgoRESUMEN
Previous studies have shown that public parks provide extraordinary habitats for ticks and tick-borne pathogens. Therefore, the aim of this study was to investigate the tick abundance (ticks/100 m(2)) in urban areas and the prevalence of Anaplasma phagocytophilum. Collection of ticks was performed by the flagging method in selected Bavarian public parks in a 2-year survey. DNA from 30 ticks of each developmental stage, sampling site and month was extracted and screened by specific real-time PCR for A. phagocytophilum. Selected positive samples were further genetically differentiated by nested PCR, targeting the 16S rRNA gene. A total of 13,403 Ixodes ricinus were collected with an average tick abundance of 15-53 ticks/100 m(2) in 2009 and 15-35 ticks/100 m(2) in 2010, depending on the sampling site. DNA of A. phagocytophilum was detected in 11.6% (n=146) and 8.5% (n=50) of adult females, 13.3% (n=164) and 9.2% (n=51) of adult males as well as 5% (n=60) and 3.9% (n=29) of nymphs for 2009 (n=3685) and 2010 (n=1884), respectively. 16S rRNA gene analysis revealed 6 different genetic variants, 2 of which were 100% identical to known sequences in humans. The results give strong evidence that the occurrence of A. phagocytophilum in I. ricinus is highly variable in different habitat types due to geographical, climatic, and biological factors as well as different genetic variants of A. phagocytophilum circulated in ticks with a noticeable habitat and host tropism.
Asunto(s)
Anaplasma phagocytophilum/aislamiento & purificación , Ehrlichiosis/epidemiología , Ixodes/microbiología , Infestaciones por Garrapatas/epidemiología , Anaplasma phagocytophilum/genética , Animales , Secuencia de Bases , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Ehrlichiosis/microbiología , Femenino , Alemania/epidemiología , Humanos , Ixodes/crecimiento & desarrollo , Masculino , Datos de Secuencia Molecular , Prevalencia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , Infestaciones por Garrapatas/parasitología , Población UrbanaRESUMEN
OBJECTIVE: Complaints of cognitive dysfunction are frequent among cancer patients. Many studies have identified neuropsychological compromise associated with cancer and cancer therapy; however, the neuropsychological compromise was not related to self-reported cognitive dysfunction. In this prospective study, the authors examined if confounding factors masked an underlying association of self-perceived cognitive function with actual cognitive performance. Determinants of self-perceived cognitive dysfunction were investigated. METHODS: Self-perceived cognitive function and cognitive performance were assessed before treatment, at the end of treatment, and 1 year after baseline in 101 breast cancer patients randomized to standard versus intensified chemotherapy. Linear mixed-effects models were applied to test the relationships of performance on neuropsychological tests, patient characteristics, and treatment variables to self-reported cognitive function. Change of cognitive performance was tested as a predictor of change in self-reports. RESULTS: Self-perceived cognitive function deteriorated during chemotherapy and had partially recovered 1 year after diagnosis. The personality trait negative affectivity, current depression, and chemotherapy regimen were consistently related to cognitive self-reports. No significant associations with performance in any of the 12 cognitive tests emerged. Change of cognitive performance was not reflected in self-reports of cognitive function. CONCLUSIONS: Neuropsychological compromise and self-perceived cognitive dysfunction are independent phenomena in cancer patients. Generally, cancer-associated neuropsychological compromise is not noticed by affected patients, but negative affectivity and treatment burden induce pessimistic self-appraisals of cognitive functioning regardless of the presence of neuropsychological compromise. Clinicians should consider this when determining adequate therapy for patients who complain of 'chemobrain'.